There is strong evidence that CD4+CD25+Foxp3+ regulatory T (Treg) cells are generated intrathymically in response to self-peptides. Yet, Treg cells also modify immune responses to infectious agents, and how selfpeptide- specific Treg cells can recognize and modify anti-pathogen immune responses, including B and T cell memory formation, is currently unknown. In preliminary studies we have found that Treg cells that are generated based on their specificity for the influenza virus hemagglutinin when it is expressed as a selfantigen in transgenic mice can modulate immune responses to influenza virus. This project will test the hypothesis that Treg cells that have been generated based on specificity for self-peptides can modulate immune responses to influenza virus following activation by crossreactive viral peptides, by bacterial peptides, or by self-peptides at the site of infection. Aim 1 will determine how such Treg cell activity impacts anti-influenza virus immunity. The ability of Treg cells to modulate the development of protective antibody responses following influenza virus vaccination, and how their activity can affect virus clearance, anti-viral immunity and the inflammation and tissue damage that are induced by influenza virus infection will be assessed. Aim 2 will determine how infection can modify the representation and activity of Treg cells. Whether influenza virus infection induces short- or long-term changes in the Treg cell repertoire, and the extent to which Treg cell activation in response to influenza virus infection can alter the immune response to a concurrent or subsequent bacterial infection (or vice versa) will be examined. Aim 3 will determine how TCR specificity for viral and/or self-peptides can guide Treg cell activity in infected hosts. Whether activation of self-peptide-specific Treg cells by weakly crossreactive viral peptides can modify the immune response to influenza virus infection will be examined, and the ability of self-peptides to activate Treg cells to modify the immune response to influenza virus infection will be assessed. The long-term goal is to determine whether and how Treg cell activity might be modified to enhance vaccination and/or limit the morbidity and mortality caused by influenza virus infection.